Abstract
Self-replicating single-stranded RNA viruses such as alphaviruses, flaviviruses, measles viruses, and rhabdoviruses provide efficient delivery and high-level expression of therapeutic genes due to their high capacity of RNA replication. This has contributed to novel approaches for therapeutic applications including vaccine development and gene therapy-based immunotherapy. Numerous studies in animal tumor models have demonstrated that self-replicating RNA viral vectors can generate antibody responses against infectious agents and tumor cells. Moreover, protection against challenges with pathogenic Ebola virus was obtained in primates immunized with alphaviruses and flaviviruses. Similarly, vaccinated animals have been demonstrated to withstand challenges with lethal doses of tumor cells. Furthermore, clinical trials have been conducted for several indications with self-amplifying RNA viruses. In this context, alphaviruses have been subjected to phase I clinical trials for a cytomegalovirus vaccine generating neutralizing antibodies in healthy volunteers, and for antigen delivery to dendritic cells providing clinically relevant antibody responses in cancer patients, respectively. Likewise, rhabdovirus particles have been subjected to phase I/II clinical trials showing good safety and immunogenicity against Ebola virus. Rhabdoviruses have generated promising results in phase III trials against Ebola virus. The purpose of this review is to summarize the achievements of using self-replicating RNA viruses for RNA therapy based on preclinical animal studies and clinical trials in humans.
Highlights
Drug development has strongly contributed to finding superior therapeutic efficacy, there is still space and need for further improvement
RNA-based drugs have been classified by mechanisms of action including antisense approaches of inhibition of messenger RNAs (mRNAs) translation, gene silencing with RNA interference, catalytically active ribozymes, protein binding RNA molecules, and aptamers for diagnostic and therapeutic applications
The common feature of self-replicating RNA viruses relates to their single-stranded RNA
Summary
Drug development has strongly contributed to finding superior therapeutic efficacy, there is still space and need for further improvement. In addition to classic drug screening of small molecules, innovative modern approaches in biotechnology and genomics research have contributed to new therapeutic possibilities in the areas of vaccine development and gene and immunotherapy In this context, RNA-based therapeutics have become an interesting alternative [1]. RNA-based drugs have been classified by mechanisms of action including antisense approaches of inhibition of mRNA translation, gene silencing with RNA interference, catalytically active ribozymes, protein binding RNA molecules, and aptamers for diagnostic and therapeutic applications In this context, lipid-encapsulated nanoparticles containing double-stranded small interfering RNA (siRNA) have been applied for binding to transthyretin (TTR) mRNA causing degradation of TTR deposits present in patients with hereditary TTR-mediated amyloidosis [2]. Vectors are described and their applications for preclinical studies and clinical trials are discussed
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